Brk (Breast tumor kinase) is also referred to as PTK6 (protein tyrosine kinase 6), and is a non-receptor tyrosine kinase which belongs to FRK (Fyn-related kinase)/PTK6 family kinases which are tyrosine kinases. Brk is coded by 451 amino acids. Brk was identified from human normal melanocytes in the first place, and immediately after that, Brk was identified in breast cancer. Brk is highly expressed in a lot of tumors including breast cancer, ovarian cancer, colon cancer, pancreatic cancer, bladder cancer, esophageal cancer, gastric cancer, non-small-cell lung cancer, prostate cancer, oral squamous cell cancer, head and neck squamous cell cancer, melanoma, B-cell lymphoma, and T-cell lymphoma. In particular, Brk is a poor prognostic factor in breast cancer, prostate cancer, nasopharyngeal cancer, and non-small-cell lung cancer. In addition, it is thought that Brk plays important roles in tumorigenesis such as promotion of proliferation, migration, and invasion of cancer cells, and avoidance of cell death (see Non Patent Literatures 1 to 7).
Accordingly, it is thought that a compound which inhibits activation of Brk is useful for treating various types of cancer.
On the other hand, it has been described in Patent Literature 1 that, a compound of the following general formula (A) or a pharmaceutically acceptable salt or a derivative thereof is used for treatment or amelioration of one or more symptoms of α-synuclein toxicity, ca-synuclein mediated diseases, or diseases in which α-synuclein fibrils are a symptom or cause of the disease.
The general formula (A) is as follows:
(wherein:each XA is independently N or CH;R1 A and ZA are each independently R5 A, C(O)R5 A or the like;R2 A and R3 A are each independently H, halo, R5 A, OR5 A, OC(O)R5 A or the like;R4 A is independently H, halo, NR5 A R5 A, NR5 A R6 A or the like; or optionally substituted alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and each of R5 A and R6 A is independently H, or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl (the definition of groups is partly extracted)).
In addition, it has been described in Patent Literature 2 a method of treating a subject for a disorder characterized by impaired protein trafficking, comprising administering to the subject an effective amount of a compound represented by general formula (B) or a pharmaceutically acceptable salt thereof, wherein the disorder is not a synucleinopathy.
The general formula (B) is as follows:
(wherein:each XB is independently N, CH or C(C1-C4 alkyl);each X1 B is independently N, NR3 B, CH or C(C1-C4 alkyl);R1 B and ZB are each independently R5 B, C(O)R5 B or the like; or, NR1 B ZB, taken together, is N═CH—NR5 B R5 B;R2 B and R3 B are each independently H, halo, R5 B or the like;R4 B is independently H, halo, NR5 B R5 B, NR5 B R6 B or the like;or optionally substituted alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;and each of R5 B and R6 B is independently H, or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl (the definition of groups is partly extracted)).
Further, it has been described in Patent Literature 3 that a compound of the following formula (C) or a tautomer or pharmaceutically acceptable salt thereof is used for treating Syk and/or JAK related diseases such as cardiac disease, inflammatory disease, immune-related disease, and cell proliferative disorder.
The general formula (C) is as follows:
a compound having:
([wherein,Y1 a C is selected from the group consisting of N, CH and C;Z1 a C is selected from the group consisting of a bond, —SO2—, —CO—, and the like;R1 a C is selected from the group consisting of: (a) H, (b) C1-8 alkyl that may be substituted with 1 to 3 substituents selected from the group consisting of amino, hydroxy, C1-8 alkoxy and the like, (c) C3-8 cycloalkyl that may be substituted with 1 to 3 amino substituents, (d) aryl that may be substituted with 1 to 3 substituents selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino and the like, (e) heterocyclyl, halogen, cyano that may be substituted with 1 to 3 substituents selected from the group consisting of: C1-8 alkyl, oxo and the like, cyano C1-6 alkylcarbonyl, aminocarbonyl and the like, and (f) heteroaryl that may be substituted with 1 to 3 substituents selected from the group consisting of C1-8 alkyl, C1-8 alkylsulfonyl and the like;R2 a C is H or C1-8 alkyl or the like;R3 a C is H or C1-8 alkyl or the like;R4 a C is selected from the group consisting of: (a) aryl that may be substituted with 1 to 3 substituents R4 c C, each of which is independently selected from the group consisting of: C1-8 alkoxy, amino, C1-8 alkylcarbonyl and aminocarbonyl C1-8 alkoxy, (b) heteroaryl, heterobicyclic C1-8 alkyl, halo, hydroxyl that may be substituted with 1 to 3 substituents R4 c C, each of which is independently selected from the group consisting of: C1-8 alkyl, halogen, hydroxyl, oxo C1-8 alkoxy and ═S, (c) heterocyclyl that may be substituted with 1 to 3 substituents R4 c C, each of which is independently selected from the group consisting of: C1-8 alkyl and oxo;R4 b C is selected from the group consisting of: H, C1-8 alkyl, C1-8 alkylcarbonyl, C1-8 alkylcarbonylamino, C1-8 alkylsulfonyl, C1-8 alkylsulfinyl, C1-8 alkylthio, C1-8 alkoxy, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonyl, amino, aminocarbonyl, aminosulfonyl, aminocarbonyl C1-8 alkoxy, amino C1-8 alkylene, carboxy, C3-8 cycloalkylcarbonylamino, C3-8 cycloalkylcarbonyl, halo, hydroxy, oxo and heterocyclyl;when R4 b C is heterocyclyl, it may be substituted with 1 to 3 substituents R4 d C independently selected from the group consisting of: C1-8 alkyl, C1-8 alkoxy, hydroxy, amino, halo, cyano, oxo and the like;R5 a C is selected from the group consisting of H, C1-8 alkyl and the like;R6 a C is selected from the group consisting of H, C1-8 alkyl and the like;R7 a C is selected from the group consisting of H, C1-8 alkyl, C3-8 cycloalkyl, and aryl and the like, each of aryl and heteroaryl may be substituted with halo, C1-8 alkyl, C1-8 alkoxy, cyano, amino, hydroxyl, heteroaryl; and the dashed line indicates a double bond or a single bond] or a tautomer or a pharmaceutically acceptable salt thereof (the definition of groups is partly extracted)).
However, none of the Patent Literatures describe or suggest a compound which is selective for Brk.